Buspirone improves 6-hydroxydopamine-induced catalepsy through stimulation of nigral 5-HT 1A receptors in rats
Alireza M. Nayebi1,2, Siyamak R. Rad3, Mehdi Saberian2, Saeid Azimzadeh2, Morteza Samini3
Drug Applied Research Center, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz 51664, Iran
!Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University of Tehran, Iran Correspondence:Alireza M. Nayebi, e-mail: nayebia@yahoo.com
Abstract:
Receptors for 5-HT1Aare widely distributed throughout the basal ganglia, and their activation results in an inhibition of dopamine (DA) release. This study aimed to investigate the effect of buspirone, as a partial agonist of 5-HT1Areceptors, on 6-hydr- oxydopamine (6-OHDA)-induced catalepsy in male Wistar rats. Catalepsy was induced by unilateral infusion of 6-OH-DA (6 µg/
2 µl/rat) into the central region of the substantia nigra pars compacta (SNc) and assayed by the bar-test method 60, 120 and 180 min after drug administration. The results demonstrated that intraperitoneal (ip) injection of buspirone at doses of 5, 7.5 and 10 mg/kg de- creased catalepsy compared with the control group. In addition, intra-SNc injection of 8-hydroxy-2-[di-n-propylamino]tetralin (8-OH-DPAT; 10 µg/rat), a 5-HT1A receptor agonist, decreased 6-OHDA-induced catalepsy. The effects of buspirone (7.5 mg/kg, ip) and 8-OH-DPAT (10 µg/rat, intra-SNc) were abolished by 1-(2-methoxyphenyl)-4-[4-(2-phthalimido) butyl]piperazine hydro- bromide (NAN-190; 10 µg/rat, intra-SNc), a 5-HT1Areceptor antagonist. Our study indicates that buspirone improves catalepsy in a 6-OHDA-induced animal model of Parkinson’s disease through activation of nigral 5-HT1Areceptors. However, further investiga- tions should be undertaken to clarify the exact mechanism of interaction between 5-HT1Aand DA receptors.
Key words:
buspirone, 5-HT )receptor, 6-hydroxydopamine, catalepsy, rat
Introduction
Parkinson’s disease is a neurodegenerative condition mainly caused by degeneration of dopaminergic neu- rons from the substantia nigra pars compacta. This re- sults in a decrease in dopamine (DA) release in the corpus striatum, the brain area that receives projec- tions from the nigral dopaminergic neurons. The most
prominent parkinsonian symptoms are tremor, rigid- ity, and bradykinesia [27]. Other neurotransmitter sys- tems also show signs of degeneration or hyperinner- vation, among which is the serotonergic system [6, 34]. Serotonergic projections originating from the dorsal raphe nuclei innervate all parts of the basal ganglia [22]. It is therefore plausible that serotonin plays a role in the regulation of movements executed by the basal ganglia.
5-HT1Areceptors are widely distributed throughout the basal ganglia [25]. They are located on dorsal ra- phe neurons that have efferents to the striatum, as well as on cortical neurons that send glutamatergic projec- tions to the basal ganglia [21]. Studies have shown that 5-HT1Areceptor stimulation exerted antiparkin- sonian effects in 6-OHDA-lesioned rats [4, 10, 14].
This effect is most likely caused by an increase in 5-HT1Areceptor activation, resulting in an inhibition of serotonin release [33]. Stimulation of 5-HT1Are- ceptors is associated with an increase in DA turnover [17], dopaminergic cell firing [1] and DA release [19], suggesting that 5-HT1Aagonists might have potential therapeutic value for the treatment of Parkinson’s dis- ease. However, other studies have reported that ad- ministration of a 5-HT1Aagonist did not affect basal DA release in the nucleus accumbens or the striatum [8, 24]. It has been shown that 5-HT1Areceptor agonists ameliorate movement disorder via non-dopaminergic systems in rats with unilateral 6-OHDA-generated le- sions [25]. Stimulation of this receptor may act to nor- malize excessive glutamate levels and play a central role in synaptic plasticity [9].
Buspirone acts as 5-HT1Areceptor partial agonist and has been utilized to treat anxiety disorders [23].
A few reports have suggested that buspirone decreases antipsychotic and D9-tetrahydrocannabinol-induced catalepsy in preclinical [11, 32, 38] as well as clinical settings [15]. Thus, whether buspirone could act as an antiparkinsonian drug in an animal model of Parkin- son’s disease is of interest. In the present study, we in- vestigated effect of buspirone on catalepsy induced by 6-OHDA, and the possible involvement of 5-HT1Are- ceptors in mediating this effect.
Materials and Methods
Animals
The experiments were carried out on male Wistar rats weighing 200–220 g. Animals were housed in stan- dard polypropylene cages, four per cage, under a 12:12 h light/dark schedule at an ambient tempera- ture of 25 ± 2°C and were allowed food and water.
Animals were acclimated to the testing conditions for 2 days before the behavioral experiment was con- ducted. All of the procedures were carried out under the ethical guidelines of the Tabriz University of
Medical Sciences and the study received approval from the Ethics Committee of the Tabriz University of Medical Sciences, according to the guide for the care and use of laboratory animals (National Institutes of Health Publication No 85–23, revised 1985).
Chemicals
All chemicals were obtained from Sigma Chemical Co. (USA) except for buspirone, which was purchased from Heumann Co. (Germany).
Solutions were prepared fresh on the days of ex- perimentation. Buspirone, 8-hydroxy-2-[di-n-propyl- amino]tetralin (8-OH-DPAT) and 1-(2-methoxyphenyl)- 4-[4-(2-phthalimido) butyl]piperazine hydrobromide (NAN-190) were dissolved in physiological saline (0.9% NaCl), and 6-OHDA was dissolved in 0.9% sa- line containing 0.2% (w/v) ascorbic acid. The drugs were injected into the central region of the substantia nigra pars compacta (SNc) in a total volume of 2 µl/rat with a constant injection rate of 0.2 µl/min.
Surgical procedures
Animals were anesthetized by intraperitoneal (ip) in- jection of sodium thiopental (40 mg/kg), and addi- tional anesthetics (4 mg/kg,ip) were given when nec- essary. After they were deeply anesthetized (loss of corneal and toe pad reflexes), rats were mounted in a stoelting stereotaxic frame in the flat skull position.
The scalp was shaved, swabbed with iodine and a central incision made to expose the skull. A cannula (23 gauge stainless steel) was implanted to serve as a guide for subsequent insertion of the injection tube into the SNc. The coordinates for these sites were based on the rat brain atlas [30]: anteroposterior (AP) –5.0 mm from the bregma; mediolateral (ML) –2.1 mm from the midline and dorsoventral (DV) –7.7 from the skull. The guide cannula was then secured to the cra- nium with dental cement. Sham-operated animals were submitted to the same procedure but 2 µl vehicle (0.9% saline containing 0.2% (w/v) ascorbic acid) of 6-OHDA was infused into the SNc.
Histology
All rats with guide cannulae were sacrificed at the end of the experiments. The brain was dissected from all animals to confirm the exact implantation of the guide cannula into the SNc. The brains were fixed in 10%
Buspirone decreases 6-OHDA-induced catalepsy
Alireza M. Nayebi et al.
tests where the tip of the injecting tube was within the SNc area were used for statistical analysis.
Lesion of dopaminergic neurons
To induce dopaminergic lesion, 6-OHDA was injected unilaterally into the SNc through implanted guide can- nula at a dose of 6 µg/2 µl/rat at a rate of 0.2 µl/min.
6-OHDA-lesioned rats were submitted to subsequent experiments after recovering from surgery for 5 days.
Catalepsy test
Catalepsy was assessed by means of a standard bar test, which measured the time the rats maintained an imposed position with both front limbs extended and resting on a 9 cm high wooden bar (0.9 cm in diame- ter). The end point of catalepsy was considered to oc- cur when both front paws were removed from the bar or if the animal moved its head in an exploratory man- ner. The cut-off time for the test was 720 s. This test was carried out 60, 120 and 180 min after drug ad- ministration. All observations were made between 9 a.m. and 4 p.m. by an observer who was blind to the nature of the treatments.
Statistical analysis
Descriptive statistics and comparisons of differences between each data set were calculated using Sigma- Stat software. The data were expressed as the mean
± SEM and were analyzed by one-way ANOVA in each experiment. Statistical significance was accepted
Results
6-OHDA induced catalepsy
Rats were divided into three groups: normal, sham- operated (receiving 2 µl vehicle) and 6-OHDA (6 µg/2 µl/rat)-injected. Drugs and vehicle were injected into the SNc through the implanted guide cannula. As shown in Figure 1, 6-OHDA was able to induce sig- nificant (p < 0.05 and 0.01) catalepsy in comparison with both normal and sham-operated rats.
Effect of buspirone on 6-OHDA induced catalepsy
Four groups of 6-OHDA-lesioned rats received saline or one of three different doses of buspirone (5, 7.5 and 10 mg/kg,ip), respectively. The results indicated that buspirone attenuated the severity of 6-OHDA induced catalepsy (p < 0.05) (Fig. 2).
Effect of 8-OH-DPAT on 6-OHDA induced catalepsy
In 6-OHDA lesioned rats that were treated with 8-OH-DPAT (10 µg/rat, intra-SNc) the elapsed time until catalepsy was significantly decreased (p < 0.05), identical to the buspirone (7.5 mg/kg,ip) treated group.
There was not any significant (p > 0.05) difference
0 5 10 15 20 25 30 35 40 45
60 120 180
Time (min)
Elapsedtime(s)
Normal Sham 6-OHDA
*
Fig. 1. The results of bar test in control, sham-operated and 6-OHDA (6 µg/2 µl/rat) lesioned rats. Each bar represents the mean ± SEM of elapsed time (s), n = 8 rats for each group; * p < 0.05 and ** p < 0.01 when compared with normal and sham- operated groups
between 8-OH-DPAT- (10 µg/rat, intra-SNc) and bus- pirone- (7.5 mg/kg,ip) treated animals (Fig. 3).
Effect of NAN-190 co-treatment with buspirone and 8-OH-DPAT on 6-OHDA-induced catalepsy
Five groups of 6-OHDA-lesioned animals respec- tively received saline, 8-OH-DPAT (10 µg/rat, intra- SNc), 8-OH-DPAT (10 µg/rat, intra-SNc) and NAN-190 (10 µg/rat, intra-SNc), buspirone (7.5 mg/kg,ip) or buspi- rone (7.5 mg/kg,ip) with NAN-190 (10 µg/rat, intra-SNc).
The results showed that the catalepsy-ameliorating effect of both 8-OH-DPAT and buspirone was abolished (p <
0.05) by NAN-190 (Fig. 4).
Discussion
We investigated the potential anticataleptic effects of drugs that act on 5-HT1A receptors in 6-OHDA- lesioned rats. The results showed that intra-SNc injec- tion of 6-OHDA induced catalepsy when assessed by
the bar test, which is a standard test that is frequently used for evaluating catalepsy induced by 6-OHDA and neuroleptic drugs in rodents [31, 37]. Buspirone, a partial agonist of 5-HT1Areceptors, improved cata- lepsy in 6-OHDA- lesioned rats. This is in accordance with previous studies reporting a promising role for 5-HT1Aagonists in decreasing the motor disorders as- sociated with Parkinson’s disease [3, 4, 26].
It has been shown that 5-HT1Areceptors are pres- ent on dorsal raphe neurons with efferents to the stria- tum and on cortical neurons that send glutamatergic projections to the basal ganglia [7, 21, 36]. Stimula- tion of 5-HT1Areceptors in these regions leads to do- pamine release [19]via the inhibition of adenyl cy- clase and the opening of potassium channels [18].
These findings indicate that modulation of 5-HT transmission by 5-HT1A receptor agonists may be a potential therapeutic approach in Parkinson’s disease.
The mechanism by which buspirone exerts an anti- cataleptic effect in lesioned animals was studied using 5-HT1Areceptor agonist and antagonists in conjunction with the drug. Buspirone is a partial agonist of 5-HT1A receptors that also has D2and a2-adrenoceptor block-
Buspirone decreases 6-OHDA-induced catalepsy
Alireza M. Nayebi et al.
0 5 10 15 20 25 30 35 40 45
60 120 180
Time (min)
Elapsedtime(s)
Saline 8-OH-DPAT Buspirone 7.5
* * * * *
*
Fig. 3. The results of bar test in 6-OHDA-lesioned rate treated with sa- line, 8-OH-DPAT (10 µg/rat, intra-SNc) and buspirone (7.5 mg/kg, ip). Each bar represents the mean ± SEM of elapsed time (s), n = 8 rat for each group; * p < 0.05 when compared with saline group
0 5 10 15 20 25 30 35 40 45
60 120 180
Time (min)
Elapsedtime(s)
Saline Buspirone 5 Buspirone 7.5 Buspirone 10
* * * *
*
*
* *
*
Fig. 2. The results of bar test in 6-OHDA-lesioned rate treated with sa- line and buspirone (5, 7.5 and 10 mg/kg, ip). Each bar represents the mean ± SEM of elapsed time (s), n = 8 rat for each group; * p < 0.05 when com- pared with saline group
ing effects [16, 20]. Thus, it is necessary to consider the possibility of involvement of these receptors in the observed effects. According to our results, 8-OH- DPAT improved 6-OHDA-induced catalepsy in a fash- ion identical to buspirone. The catalepsy-improving effect of both buspirone and 8-OH-DPAT were re- versed by NAN-190, a 5-HT1Areceptor antagonist.
These findings confirm the involvement of 5-HT1A receptors in the observed effect of buspirone.
Therefore, we suggest that buspirone alleviates cata- lepsy in 6-OHDA-lesioned by acting on 5-HT1Arecep- tors in the SNc, and could potentially be used as an adju- vant therapy together with routinely used antiparkin- sonian drugs.
Convergent evidence suggests that 5-HT1Arecep- tor agonists could be used prophylactically to reduce L-DOPA-induced dyskinesia by way of stimulating 5-HT1Ainhibitory autoreceptors within the raphe nu- clei, which may normalize the amount of DA deliv- ered to the striatum [2, 5, 28, 29]. However, their beneficial effect in reducing motor symptoms as well as improving efficacy of other antiparkinsonian drugs, such as dopamine receptor agonists, monoamine oxi- dase B (MAOB) and catechol-O-methyltransferase (COMT) inhibitors, has not been described clearly.
Apart from the observed anticataleptic effect, buspi- rone has a prominent anxiolytic effect and is used for managing some psychiatric disorders [12, 35]. Since anxiety is one of the most common psychiatric prob- lems experienced by parkinsonian patients [13], adju- vant therapy with buspirone or other partial agonists of 5-HT1Areceptor may offer an appealing strategy
for improving the efficacy of antiparkinsonian drugs while taking advantage of these anxiolytic effects.
Typical antipsychotics such as haloperidol, a D2re- ceptor blocker, are known to induce extrapyramidal side-effects in patients [15]. These effects can be modeled in rodents by measuring catalepsy. It has been reported that selective serotonin reuptake inhibi- tors attenuate antipsychotic-induced catalepsy in mice [31]. We have demonstrated that buspirone alleviated 6-OHDA-induced catalepsy by affecting nigral 5-HT1A receptors. This confirms the results of another study showing that 5-HT1A receptor agonists decrease haloperidol-induced catalepsy [32]. This suggests that co-administration of a 5-HT1Aagonist with a D2 re- ceptor antagonist may have a lower propensity to in- duce extrapyramidal side effects.
In conclusion, our data suggest that buspirone alle- viates catalepsy in 6-OHDA-lesioned rats and that this effect is exerted through stimulation of nigral 5-HT1Areceptors. In addition, we suggest that investi- gation of a possible clinical application of the buspi- rone should be carried out to test whether it is useful in increasing the efficacy or decreasing motor side ef- fects of antiparkinson and typical antipsychotic (D2 antagonist) drugs. Further studies are needed to eluci- date the exact mechanism of buspirone on neuronal systems that are responsible to its anticataleptic effect.
Acknowledgment:
We wish to thank the Director of Drug Applied Research Center, Tabriz University of Medical Sciences for supporting this study.
0 5 10 15 20 25 30 35 40
60 120 180
Time (min)
Elapsedtime(s)
Buspirone 7.5 Buspirone7.5+NAN-190
# *
(7.5 mg/kg, ip) on catalepsy induced by 6-OHDA. Each bar represents the mean
± SEM of elapsed time (s), n = 8 rat for each group; * p < 0.05 when compared with 8-OH-DPAT group, # p < 0.05 when compared with buspirone 7.5 group
References:
1. Arborelius L, Chergui K, Murase S, Nomikos GG, Hook BB, Chouvet G, Hacksell U et al.: The 5-HT1Areceptor selective ligands, (R)-8-OH-DPAT and (S)-UH-301, dif- ferentially affect the activity of midbrain dopamine neu- rons. Naunyn Schmiedebergs Arch Pharmacol, 1993, 347, 353–362.
2. Ba M, Kong M, Ma G, Yang H, Lu G, Chen S, Liu Z:
Cellular and behavioral effects of 5-HT1A receptor ago- nist 8-OH-DPAT in a rat model of levodopa-induced mo- tor complications. Brain Res, 2007, 1127, 177–184.
3. Bara-Jimenez W, Bibbiani F, Morris MJ, Dimitrova T, Sherzai A, Mouradian MM, Chase TN: Effects of sero- tonin 5-HT1A agonist in advanced Parkinson’s disease.
Mov Disord, 2005, 20, 932–936.
4. Bezard E, Gerlach I, Moratalla R, Gross CE, Jork R:
5-HT1Areceptor agonist-mediated protection from MPTP toxicity in mouse and macaque models of Parkinson’s disease. Neurobiol Dis, 2006, 23, 77–86.
5. Bishop C, Krolewski DM, Eskow KL, Barnum CJ, Du- pre KB, Deak T, Walker PD: Contribution of the striatum to the effects of 5-HT1A receptor stimulation in
L-DOPA-treated hemiparkinsonian rats. J Neurosci Res, 2009, 87, 1645–1658.
6. Brown P, Gerfen CR: Plasticity within striatal direct pathway neurons after neonatal dopamine depletion is mediated through a novel functional coupling of sero- tonin 5-HT2receptors to the ERK 1/2 map kinase path- way. J Com Neurol, 2006, 498, 415–430.
7. Burnet PW, Eastwood SL, Lacey K, Harrison PJ: The distribution of 5-HT1Aand 5-HT2Areceptor mRNA in human brain. Brain Res, 1995, 676, 157–168.
8. De Deurwaerdere P, Navailles S, Berg KA, Clarke WP, Spampinato U: Constitutive activity of the serotonin2C receptor inhibitsin vivo dopamine release in the rat striatum and nucleus accumbens. J Neurosci, 2004, 24, 3235–3241.
9. Dupre KB, Eskow KL, Barnum CJ, Bishop C: Striatal 5-HT1Areceptor stimulation reduces D1 receptor-induced dyskinesia and improves movement in the hemiparkin- sonian rat. Neuropharmacology, 2008, 55, 1321–1328.
10. Dupre KB, Eskow KL, Negron G, Bishop C: The differ- ential effects of 5-HT1Areceptor stimulation on dopa- mine receptor-mediated abnormal involuntary move- ments and rotations in the primed hemiparkinsonian rat.
Brain Res, 2007, 1158, 135–143.
11. Egashira N, Matsuda T, Koushi E, Mishima K, Iwasaki K, Shoyama Y, Fujiwara M: Involvement of 5-hydr- oxytryptamine1Areceptors inD9-tetrahydrocannabinol- induced catalepsy-like immobilization in mice. Eur J Pharmacol, 2006, 550, 117–122.
12. Filip M, Bader M: Overview on 5-HT receptors and their role in physiology and pathology of the central nervous system. Pharmacol Rep, 2009, 61, 761–777.
13. Forjaz MJ, Rodriguez-Blázquez C, Martinez-Martin P;
on behalf of the Longitudinal Parkinson’s Disease Pa- tient Study (Estudio Longitudinal de Pacientes con En- fermedad de Parkinson-ELEP) Group:Rasch analysis of the hospital anxiety and depression scale in Parkinson’s disease. Mov Disord, 2008, 24, 525–531.
14. Gerber R, Alter CA, Leibman JM: Rotational behavior induced by 8-hydroxy-DPAT, a putative 5-HT1Aagonist, in 6-hydroxydopamine-lesioned rats. Psychopharmacol- ogy (Berl), 1988, 94, 178–182.
15. Goff DC, Midha KK, Brotman., McCormick S, Waites M, Mmico ET: An open trial of buspirone added to neu- roleptics in schizophrenic patients, J Clin Psychopharma- col, 1991, 11, 193–197.
16. Gower AJ, Tricklebank MD: Alpha 2-adrenoceptor an- tagonist activity may account for the effects of buspirone in an anticonfilict test in the rat. Eur J Pharmacol, 1988, 155, 129–137.
17. Hamon M, Fattaceini CM, Adrien J, Gallissot MC, Mar- tin P, Gozlan H: Alterations of central serotonin and do- pamine turnover in rats treated with ipsapirone and other 5-hydroxytryptamine1Aagonists with potential anxiolytic properties. J Pharmacol Exp Ther, 1988, 246, 745–752.
18. Harrington MA, Oksenberg D, Peroutka SJ: 5-Hydr- oxytryptamine1Areceptors are linked to a Gi-adenylate cyclase complex in rat hippocampus. Eur J Pharmacol, 1988, 154, 95–98.
19. Ichikawa J, Meltzer HY: R(+)-8-OH-DPAT, a sero- tonin1Areceptor agonist, potentiated S(–)-sulpiride- induced dopamine release in rat medial prefrontal cortex and nucleus accumbens but not striatum. J Pharmacol Exp Ther, 1999, 291, 1227–1232.
20. Jadhav SA, Gaikwad RV, Gaonkar RK, Thorat VM, Gur- sale SC, Balsara JJ: Dose-dependent response of central dopaminergic systems to buspirone in mice. Indian J Exp Biol, 2008, 46, 704–714.
21. Knobelman DA, Kung HF, Lucki I: Regulation of extra- cellular concentrations of 5-hydroxytryptamine (5-HT) in mouse striatum by 5-HT1Aand 5-HT1Breceptors.
J Pharmacol Exp Ther, 2000, 292, 1111–1117.
22. Lavoie B, Parent A: Immunohistochemical study of the serotoninergic innervations of the basal ganglia in the squirrel monkey. J Comp Neurol, 1990, 299, 1–16.
23. Lim LW, Temel Y, Visser-Vandewalle V, Steinbusch H, Schruers K, Hameleers R, Esquivel G et al.: Effect of buspirone on the behavioral regulation of rats in low ver- sus high anxiety conditions. Arzneimittelforschung, 2008, 58, 269–276.
24. Lucas G, Bonhomme N, De Deurwaerdere P, Le Moal M, Spampinato U: 8-OH-DPAT, a 5-HT1Aagonist and ri- tanserin, a 5-HT2A/Cantagonist, reverse haloperidol in- duced catalepsy in rats independently of striatal dopa- mine release. Psychpharmacology, 1997, 131, 57–63.
25. Matsubara K, Shimizu K, Suno M, Ogawa K, Awaya T, Yamada T, Noda T et al.: Tandospirone 5-HT1Aagonist, ameliorates movement disorder via non-dopaminergic systems in rats with unilateral 6-hydroxydopamine- generated lesions. Brain Res, 2006, 1112, 126–133.
26. Mignon L, Wolf WA: Postsynaptic 5-HT1Areceptor stimula- tion increases motor activity in the 6-hydroxydopamine-le- sioned rat: implications for treating Parkinson’s disease.
Psychopharmacology (Berl), 2007, 192, 49–59.
27. Mink JW: The basal ganglia: focused selection and inhi- bition of competing motor programs. Prog Neurobiol, 1996, 50, 381–425.
28. Muñoz A, Li Q, Gardoni F, Marcello E, Qin C, Carlsson T, Kirik D et al.: Combined 5-HT1Areceptor agonist for Buspirone decreases 6-OHDA-induced catalepsy
Alireza M. Nayebi et al.
inhibits L-DOPA-induced abnormal involuntary move- ments by a WAY-100635-sensitive mechanism. Psycho- pharmacology (Berl), 2009, 204, 743–754.
30. Paxinos G, Watson C: The rat brain in stereotaxic coordi- nates. Academic Press, Sydney, 1982.
31. Pires JGP, Bonikoski V, Futuro-Neto HA: Acute effects of selective serotonin reuptake inhibitors on
neuroleptic-induced catalepsy in mice. Braz J Med Biol Res, 2005, 38, 1867–1872.
32. Prinssen EP, Colpaert FC, Koek W: 5-HT1Areceptor ac- tivation and anti-cataleptic effects: high-efficacy agonists maximally inhibit haloperidol-induced catalepsy. Eur J Pharmacol, 2002, 453, 217–221.
33. Riad M, Garcia S, Watkins KC, Jodoin N, Doucet E, Langlois X, el Mestikawy S et al.: Somatodendritic lo- calization of 5-HT1A and preterminal axonal localization of 5-HT1B serotonin receptors in adult rat brain. J Comp Neurol, 2000, 417, 181–194.
35. Tunnicliff G: Molecular basis of buspirone’s anxiolytic action. Pharmacol Toxicol, 1991, 69, 149–156.
36. Wright DE, Seroogy KB, Lundgren KH, Davis BM, Jen- nes L: Comparative localization of serotonin1A, 1C and 2 receptor subtype mRNA in rat brain. J Comp Neurol, 1995, 351, 357–373.
37. Yu JG, Wu J, Shen FM, Cai GJ, Liu JG, Su DF: Arterial baroreflex dysfunction fails to mimic Parkinson’s disease in rats. J Pharmacol Sci, 2008, 108, 56–62.
38. Zazpe A, Artaiz I, Innerárity A, Del Olmo E, Castro E, Labeaga L, Pazos A et al.: In vitro and in vivo characteri- zation of F-97013-GD, a partial 5-HT1Aagonist with an- tipsychotic- and antiparkinsonian-like properties. Neuro- pharmacology, 2006, 51, 129–140.
Received:
May 15, 2009; in revised form: January 26, 2010.
